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NIHR Signal Levetiracetam is a useful alternative to phenytoin in stopping prolonged epileptic seizures in children

Published on 16 July 2019

doi: 10.3310/signal-000790

Levetiracetam is as effective as phenytoin at stopping prolonged epileptic seizures in children. In this trial, levetiracetam stopped 70% of children convulsing compared with 64% for phenytoin within 35 to 45 minutes. Adverse events were similar. This combined with the fact levetiracetam may be easier to administer safely make it an important option.

Most epileptic seizures stop by themselves within a few minutes, but sometimes they continue for much longer. If this happens emergency treatment with IV benzodiazepines is recommended. If these fail, IV phenytoin is currently the commonest drug recommended, but is a particularly complicated drug to use and has potential interactions with other drugs.

This NIHR funded study shows that levetiracetam may be preferable to phenytoin, with comparable safety and efficacy profiles but potentially simpler administration.

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Why was this study needed?

Epilepsy is caused by abnormal electrical activity in the brain. Around 1 in 200 children in the UK are affected. Seizures usually resolve without intervention within a few minutes. However, in some instances they continue, and if not treated quickly, they can be harmful. Status epilepticus, that is, prolonged or repeated seizures (without regaining consciousness between) is the second most common reason for unplanned admissions to paediatric intensive care units in the UK.

Initial management is with benzodiazepines, but if these are ineffective, phenytoin or phenobarbital are currently the recommended second-line treatment options for the condition. However, the evidence supporting this approach is not conclusive. This, combined with reports of cardiovascular safety concerns, is one of the reasons NICE highlighted management of this condition as one of the five priority research areas in its epilepsy guideline.

This NIHR-funded study sought to provide more robust evidence on use of the anticonvulsant levetiracetam, a newer alternative to phenytoin to determine which is safer or more effective.  

What did this study do?

EcLiPSE was an open-label randomised controlled trial involving 30 UK emergency departments. Children with convulsive status epilepticus that had not responded to benzodiazepine were randomised to be given intravenous levetiracetam 40mg/kg over five minutes or phenytoin 20mg/kg over at least 20 minutes. They were aged between six months and 18 years, average age three. Due to it being an emergency treatment, consent was deferred until afterwards.

This is the largest UK based trial (404 children randomised) to date evaluating the use of these two anticonvulsants. Limitations, such as the open-label design, are unlikely to have had significant impact upon the findings, because the outcome was relatively objective.

What did it find?

  • Rates of seizure termination by both drugs were similar with 106/152 (70%) children in the levetiracetam group having their seizures stopped compared with 86/134 (64%) in the phenytoin group.
  • Median time from randomisation to the end of the seizure was 35 minutes in the levetiracetam group and 45 minutes in the phenytoin group (hazard ratio 1.20, 95% CI 0.91 to 1.60).
  • Clinicians taking part in the trial reported that phenytoin was harder to use due to the calculations needed when reconstituting it, as well as the number of vials required and the additional safety checks needed for its administration.
  • 12% of children in the levetiracetam group and 14% in the phenytoin group suffered adverse events. Agitation was most common in the levetiracetam group occurring in 8% of children, whereas the phenytoin group had a broader range of events with only a few patients reporting each adverse event.
  • Five serious adverse events occurred, three in two children receiving phenytoin, one in a child receiving levetiracetam, and one in a child who received both drugs. Two of these, hypotension and increased focal seizures, were assessed as being related to treatment. These occurred in the same child who was receiving phenytoin.

What does current guidance say on this issue?

The NICE 2016 guideline Epilepsies: diagnosis and management states that for children hospitalised with convulsive status epilepticus, the following steps need to be taken immediately: their airway needs to be secured, and cardiac and respiratory function need to be assessed as do blood glucose levels. Intravenous access also needs to be made in a large vein.

Intravenous lorazepam should then be given as the first-line treatment with intravenous diazepam as the alternative. Buccal midazolam can be used if immediate intravenous access is not possible. A maximum of two doses of the first-line treatment (including pre-hospital treatment) should be given. If these fail to stop the seizures, use of intravenous phenytoin or phenobarbital as second-line treatment is recommended.

What are the implications?

This study, along with another recent Lancet trial, based in New Zealand and Australia, provides good evidence for the use of levetiracetam as an alternative second-line treatment for convulsive status epilepticus. It is easier to use and has a better safety profile.

This newer evidence can be used by staff in addition to the NICE guideline.

Citation and Funding

Lyttle MD, Rainford NEA, Gamble C et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial Lancet. 2019. Apr 17. doi: 10.1016/s0140-6736(19)30724-x. [Epub ahead of print].

This trial was funded by the NIHR Health Technology Assessment Programme (project number 12/127/134).

Bibliography

Dalziel SR, Borland ML and Furyk J. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet. 2019;393:2135-45.

NHS website. Epilepsy. London: Department of Health and Social Care; 2017.

NHS Improvement. Patient safety alert: risk of death and severe harm from error with injectable phenytoin. London: NHS Improvement; 2016.

NICE. Epilepsies: diagnosis and management. GC137. London: National Institute for Health and Care Excellence; 2016.

Why was this study needed?

Epilepsy is caused by abnormal electrical activity in the brain. Around 1 in 200 children in the UK are affected. Seizures usually resolve without intervention within a few minutes. However, in some instances they continue, and if not treated quickly, they can be harmful. Status epilepticus, that is, prolonged or repeated seizures (without regaining consciousness between) is the second most common reason for unplanned admissions to paediatric intensive care units in the UK.

Initial management is with benzodiazepines, but if these are ineffective, phenytoin or phenobarbital are currently the recommended second-line treatment options for the condition. However, the evidence supporting this approach is not conclusive. This, combined with reports of cardiovascular safety concerns, is one of the reasons NICE highlighted management of this condition as one of the five priority research areas in its epilepsy guideline.

This NIHR-funded study sought to provide more robust evidence on use of the anticonvulsant levetiracetam, a newer alternative to phenytoin to determine which is safer or more effective.  

What did this study do?

EcLiPSE was an open-label randomised controlled trial involving 30 UK emergency departments. Children with convulsive status epilepticus that had not responded to benzodiazepine were randomised to be given intravenous levetiracetam 40mg/kg over five minutes or phenytoin 20mg/kg over at least 20 minutes. They were aged between six months and 18 years, average age three. Due to it being an emergency treatment, consent was deferred until afterwards.

This is the largest UK based trial (404 children randomised) to date evaluating the use of these two anticonvulsants. Limitations, such as the open-label design, are unlikely to have had significant impact upon the findings, because the outcome was relatively objective.

What did it find?

  • Rates of seizure termination by both drugs were similar with 106/152 (70%) children in the levetiracetam group having their seizures stopped compared with 86/134 (64%) in the phenytoin group.
  • Median time from randomisation to the end of the seizure was 35 minutes in the levetiracetam group and 45 minutes in the phenytoin group (hazard ratio 1.20, 95% CI 0.91 to 1.60).
  • Clinicians taking part in the trial reported that phenytoin was harder to use due to the calculations needed when reconstituting it, as well as the number of vials required and the additional safety checks needed for its administration.
  • 12% of children in the levetiracetam group and 14% in the phenytoin group suffered adverse events. Agitation was most common in the levetiracetam group occurring in 8% of children, whereas the phenytoin group had a broader range of events with only a few patients reporting each adverse event.
  • Five serious adverse events occurred, three in two children receiving phenytoin, one in a child receiving levetiracetam, and one in a child who received both drugs. Two of these, hypotension and increased focal seizures, were assessed as being related to treatment. These occurred in the same child who was receiving phenytoin.

What does current guidance say on this issue?

The NICE 2016 guideline Epilepsies: diagnosis and management states that for children hospitalised with convulsive status epilepticus, the following steps need to be taken immediately: their airway needs to be secured, and cardiac and respiratory function need to be assessed as do blood glucose levels. Intravenous access also needs to be made in a large vein.

Intravenous lorazepam should then be given as the first-line treatment with intravenous diazepam as the alternative. Buccal midazolam can be used if immediate intravenous access is not possible. A maximum of two doses of the first-line treatment (including pre-hospital treatment) should be given. If these fail to stop the seizures, use of intravenous phenytoin or phenobarbital as second-line treatment is recommended.

What are the implications?

This study, along with another recent Lancet trial, based in New Zealand and Australia, provides good evidence for the use of levetiracetam as an alternative second-line treatment for convulsive status epilepticus. It is easier to use and has a better safety profile.

This newer evidence can be used by staff in addition to the NICE guideline.

Citation and Funding

Lyttle MD, Rainford NEA, Gamble C et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial Lancet. 2019. Apr 17. doi: 10.1016/s0140-6736(19)30724-x. [Epub ahead of print].

This trial was funded by the NIHR Health Technology Assessment Programme (project number 12/127/134).

Bibliography

Dalziel SR, Borland ML and Furyk J. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet. 2019;393:2135-45.

NHS website. Epilepsy. London: Department of Health and Social Care; 2017.

NHS Improvement. Patient safety alert: risk of death and severe harm from error with injectable phenytoin. London: NHS Improvement; 2016.

NICE. Epilepsies: diagnosis and management. GC137. London: National Institute for Health and Care Excellence; 2016.

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Published on 22 April 2019

Lyttle, M. D.,Rainford, N. E. A.,Gamble, C.,Messahel, S.,Humphreys, A.,Hickey, H.,Woolfall, K.,Roper, L.,Noblet, J.,Lee, E. D.,Potter, S.,Tate, P.,Iyer, A.,Evans, V.,Appleton, R. E.

Lancet , 2019

BACKGROUND: Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus. METHODS: This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894. FINDINGS: Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1.20, 95% CI 0.91-1.60; p=0.20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). INTERPRETATION: Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Author commentary

The study provides scientifically-robust data that will better inform paediatricians (in emergency medicine, intensive care, neurology and general paediatrics) in their management of convulsive status epilepticus in children. Specifically, it shows that either levetiracetam or phenytoin could be used as a first-choice anticonvulsant in the second-stage treatment of paediatric convulsive status epilepticus.

The decision as to which to use as the first-choice drug will be guided by additional factors including ease of preparation and administration of levetiracetam and its better safety profile, specifically its absence of potential fatal cardiac-toxicity that is a risk with phenytoin.

Richard Appleton, Department of Neurosciences, Alder Hey Children’s NHS Foundation Trust, Liverpool

The commentator declares no conflicting interests